Squalene synthetase is a microsomal enzyme which catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate (FPP) in the presence of nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) to form squalene (Poulter, C. D.; Rilling, H. C., in "Biosynthesis of Isoprenoid Compounds", Vol. I, Chapter 8, pp. 413-441, J. Wiley and Sons, 1981, and references therein). This enzyme is the first committed step of the de novo cholesterol biosynthetic pathway. The selective inhibition of this step should allow the essential pathways to isopentenyl tRNA, ubiquinone, and dolichol to proceed unimpeded. Squalene synthetase along with HMG-CoA reductase have been shown to be down-regulated by receptor mediated LDL uptake (Faust, J. R.; Goldstein, J. L.; Brown, M. S. Proc. Nat. Acad Sci U.S.A. 1979, 76, 5018-5022), lending credence to the proposal that inhibiting squalene synthetase will lead to an up-regulation of LDL receptor levels, as has been demonstrated for HMG-CoA reductase, and thus ultimately should be useful for the treatment and prevention of hypercholesterolemia and atherosclerosis.
U.S. Pat. No. 3,657,282 (Merck) (Division U.S. Pat. No. 3,822,296) discloses antibiotics of the structure ##STR2## wherein R=SO.sub.3 H, SO.sub.2 R*, H, hydrocarbyl other than alkyl (eg. alkenyl, alkynyl, phenyl and naphthyl), substituted hydrocarbyl, CO.sub.2 H, CO.sub.2 R*, SO.sub.3 NR.sub.2, heterocycle*, amino*, OH, OR, SH, SR, CHO, halogen, NO.sub.2, CN, PO.sub.3 H.sub.2, AsO.sub.3 H.sub.2, acyl, --CHR.sup.1 R.sup.3 where R.sup.1 =H, Me; R.sup.3 =R as above, preferably at least one R not=H, R preferably contains 1-10 carbons. *=optionally substituted.
Starting materials employed to prepare the above antibiotics include ##STR3## wherein R can be SO.sub.3 H, and X and Y are hydroxy or functional equivalent precursor to epoxide: eg. OH, halo, azide, RCO.sub.2 --, RSO.sub.2 O--, R.sub.2 S.sup.+ --, R.sub.3 N.sup.+ --, ArO--, R.sub.2 PO.sub.2, RSO.sub.2 NR.sup.1 --. One of X and Y must be an oxygen radical.
EP 89/0-344-980 (Smith Kline) discloses .alpha.-antagonists of the structure ##STR4## wherein Y or Z may be --SO.sub.2 R, --P(R)O(OR), --PR.sub.2 O, --PO(OR).sub.2, and amides.
WO 88/00061 (Amersham) discloses Technetium-99 complexes for Done scanning having the structure ##STR5## wherein R.sup.1 and R.sup.3 =H, SO.sub.3 H or alkyl substituted with SO.sub.3 H and optionally one or more heteroatoms; R.sup.4 can also be SO.sub.3 H or OH, NH.sub.2, NHMe, NMe.sub.2, lower alkyl substituted with a polar group; R.sup.2 =same as R.sup.4 except not SO.sub.3 H and n=0, 1.
U.S. Pat. No. 4,032,521 (Merck) discloses intermediates, in cephalosporin synthesis, of the structures ##STR6##
WO 90/07513 (Gas Research Institue) discloses electrolytes for fuel cells of the structure ##STR7## wherein R=organic radicals with 1 or more F atoms;
R.sup.1 =H, alkali metal, Zn, Cd; PA1 R.sup.2 =H, lower alkyl; PA1 r=2, 3; and x, y=1, 2, 3. PA1 n=1 to 4. PA1 D=optionally substituted, saturated or unsaturated aliphatic radical (&lt;40 carbons), can be interrupted by heteroatoms such as 0, SO.sub.2, NH, NR. PA1 W=PO.sub.3 R.sub.2, SO.sub.3 R, SO.sub.2 R, --NY--SO.sub.3 R, --SO.sub.2 NR.sub.2, --SSO.sub.3 R, CO.sub.2 R, OH, NR.sub.3 .sup.+, NR.sub.2, CONR.sub.2. PA1 2a X=Li PA1 2b X=n-Bu.sub.4 N PA1 R.sup.5a is H, alkyl, arylalkyl or aryl; PA1 R.sup.4 is H, alkyl, aryl, cycloalkyl, arylalkyl, metal ion, or other pharmaceutically acceptable salt, or prodrug ester; PA1 R.sup.1 is a lipophitic group containing at least 7 carbons; PA1 Z is H, halogen, lower alkyl or lower alkenyl. PA1 wherein R.sup.2 is OR.sup.5 or R.sup.5a ; PA1 R.sup.3 and R.sup.5 are the same or different and are H, alkyl, arylalkyl, aryl, cycloalkyl, a metal ion or other pharmaceutically acceptable cations or salts as defined below,; PA1 R.sup.5a is alkyl, arylalkyl or aryl; PA1 R.sup.4 is H, metal ion or other pharmaceutically acceptable cations or salts as defined below; PA1 Z is H, halogen, lower alkyl or lower alkenyl; PA1 R.sup.1 is a lipophilic group containing at least 7 carbons and is alkyl containing 7 to 25 carbons in the chain; alkenyl containing from 7 to 25 carbon atoms in the chain and from 1 to 6 double bonds; alkynyl containing 7 to 25 carbon atoms in the chain and from 1 to 6 triple bonds; mixed alkenyl-alkynyl containing 1 to 5 double bonds and 1 to 5 triple bonds;,aryl; cycloalkyl; cycloheteroalkyl linked through a carbon on the ring or a heteroatom; heteroaryl; heteroarylalkyl; cycloalkylalkyl; cycloheteroalkylalkyl; wherein any of the above groups may be optionally substituted; or R.sup.1 is a group of the structure ##STR17## wherein Ar is aryl (such as phenyl or naphthyl), heteroaryl (5 or 6 membered) and may include one to three additional rings fused to Ar ( such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl) and wherein (CH.sub.2).sub.p contains from 1 to 15 carbons, preferably 2 to 12 carbons, in the chain and may include 0, 1, 2 or 3 double bonds and/or 0, 1, 2 or 3 triple bonds in the normal chain, and may contain an ether or amino function in the chain, and/or may include 0, 1, 2 or 3 substituents as defined below for R.sup.6 ; and R.sup.6, R.sup.7, R.sup.8 and R.sup.8a are the same or different and are H, alkyl containing 1 to 40 carbons, preferably from 3 to 25 carbons, alkoxy containing 1 to 40 carbons, preferably from 3 to 25 carbons, alkenyl containing 2 to 40 carbons, preferably from 3 to 25 carbons, alkenyloxy containing 2 to 40 carbons, preferably from 3 to 25 carbons, alkynyl containing 2 to 40 carbons, preferably from 3 to 25 carbons, alkynyloxy containing 2 to 40 carbons, preferably from 3 to 25 carbons, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, cycloalkyl, cycloalkylalkyl, Ar-alkyl, (such as arylalkyl), ArO (such as aryloxy), Ar-amino (such as arylaminoi, hydroxy, halogen, nitro, Ar (such as aryl), amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, alkenyl, aryl or any of the Ar groups mentioned above), thiol, alkylthio, Ar-thio (such as arylthio), alkyl-sulfinyl, Ar-sulfinyl (such as arylsulfinyl), alkylsulfonyl, Ar-sulfonyl (such as arylsulfonyl), carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, Ar-carbonyloxy (such as arylcarbonyloxy), Ar-carbonylamino (such as arylcarbonylamino) or alkylcarbonylamino, as well as any of the Ar groups as defined above, and preferably wherein the total number of carbons in the substituted Ar-CH.sub.2).sub.p - group exceeds 10 carbons; PA1 R.sup.3 is H, a metal ion such as Na or K; PA1 R.sup.4 is a metal ion such as Na or K; PA1 R.sup.1 is alkenyl such as ##STR30## wherein (CH.sub.2).sub.x is defined as (CH.sub.2).sub.p above and x is preferably 2 to 8, ##STR31## m is 1 to 5; ##STR32## n=1 to 15; R.sup.11, R.sup.11a, R.sup.11b, and R.sup.11c are independently selected from H, alkyl such as propyl, halo, alkoxy, such as methoxy or propyloxy, alkenyl such as ##STR33## wherein R.sup.12, R.sup.12a and R.sup.12b are independently selected from H, aryl (such as phenyl or naphthyl), alkylphenyl (such as p-propylphenyl, p-pentylphenyl), alkyl containing 1 to 20 carbons (such as p-heptyl), halo, alkoxy (such as methoxy or propyloxy), alkenyl (such as ##STR34## arylalkyloxy (such as phenethyloxy), alkenyloxy (such as ##STR35## aryloxy (such as phenoxy), phenylalkyl (such as benzyl, phenylpropyl), alkylphenoxy (such as orthobutylphenoxy), alkenylphenyl (such as ##STR36## wherein R.sup.14 is aryl, heteroaryl, aryloxy, heteroaryloxy, cycloalkyl, heterocycloalkyl, and (CH.sub.2).sub.p' and (CH.sub.2).sub.p" are as defined above for --CH.sub.2).sub.p --. Preferred p' and p" are independently 1 to 4; EQU Ar.sup.1 --O--Ar.sup.2 --(CH.sub.2).sub.p -- PA1 where Z'=F, reagents used for fluorination include XeF.sub.2, ##STR44## Reaction Scheme E Preparation of Starting Compound VIII for Scheme B ##STR45## Scheme F Synthesis of Monoesters ##STR46## PA1 m is 0 to 8 ##STR59## R.sup.40 =H, alkyl, cycloalkyl, or aryl such as methyl, ethyl, isopropyl, pentyl, phenyl and cyclopentyl PA1 R.sup.41 =alkyl such as methyl, ethyl or halo such as Cl or F ##STR60## PA1 R.sup.2 =H, OMetal, alkyl, aryl PA1 R.sup.3 =H, metal ion or alkyl PA1 R.sup.4 =H or metal ion ##STR65## Re 158) to 160) PA1 p.sup.1 =0-8 PA1 m=2-8 PA1 R.sup.3 =H, metal ion or alkyl PA1 R.sup.4 =H, metal ion PA1 R.sup.2 =OH, Ometal, alkyl, aryl ##STR68## X is O, S, NH, SO, SO.sub.2, CR.sub.5 R.sub.6, C.dbd.O R.sub.1a, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are independently H, halogen, C.sub.1 -C.sub.5 alkyl, C.sub.1 -C.sub.5 alkenyl, C.sub.1 -C.sub.5 alkoxy, aryl, arylalkyl, aryloxy; for R.sub.5 and R.sub.6, halogen can be fluorine only; and R.sup.2, R.sup.3 and R.sup.4 are as defined previously. PA1 n=0 to 4; R.sub.1, R.sub.2, R.sub.5 and R.sub.6 are independently halogen, alkyl, alkenyl, alkoxy, aryl, H, aryloxy; for R.sup.5 and R.sup.6 halogen can be fluorine only, and R.sup.2, R.sup.3 and R.sup.4 are as defined hereinbefore.
U.S. Pat. No. 4,254,215 (Ciba Geigy AG) discloses a process for photographic developers wherein one component of a developer solution is: EQU HS-D-(W).sub.n
wherein
DE 89/3739691-A (Hoechst) (Derwent #89-173507/24) discloses herbicides and plant growth regulators of the structure ##STR8## wherein Y=CH, N; X=O, S; Z=CH, N; R.sup.1, R.sup.2 =C1-C6 alkyl or alkoxy; R.sup.3 =H, C1-C6 alkyl or alkoxy, C2-C6 alkenyl, alkynyl, alkenyloxy, alkynyloxy; all optionally substituted with one or more halogens; and R.sup.4 =H, C1-C4 alkyl or physiologically acceptable cation.
New intermediates are disclosed of the structures ##STR9##
Burton, D. J., J. Am. Chem. Soc. 1989, 111, 1773-1776 discloses electrolytes and chelators of the structures EQU (HO).sub.2 P(O)CF.sub.2 SO.sub.3 Na (HO).sub.2 P(O)CF.sub.2 SO.sub.3 H
Su, D.; Cen. W.; Kirchmeier, R. L.; Shreeve, J. M., Can. J. Chem. 1989, 67, 1795-1799, disclose electrolytes and chelators of the structures EQU (C.sub.2 H.sub.5 O).sub.2 P(O)CFBrSO.sub.3 Na (C.sub.2 H.sub.5 O).sub.2 P(O)CFHSO.sub.3 Na EQU (HO).sub.2 P(O)CFHSO.sub.3 Na (HO).sub.2 P(O)CFHSO.sub.3 H EQU (C.sub.2 H.sub.5 O).sub.2 P(O)CF(SO.sub.3 Na) (SO.sub.2 Na) EQU (C.sub.2 H.sub.5 O).sub.2 P(O)CF(SO.sub.3 Na).sub.2
Farrington, G. K.; Kumar, A.; Wedler, F. C., J. Med. Chem. 1985, 28, 1668-1673 discloses compound 10 as an inhibitor of aspartate transcarbamylase. Compound 24 is a synthetic intermediate. ##STR10##
Musicki, B.; Widlanski, T. S. Tetrahedron Lett. 1991, 32, 1267-1270 discloses compound 4 as a synthetic intermediate. ##STR11##
Carretero, J. C.; Demillequand, M.; Ghosez, L., Tetrahedron 1987, 43, 5125-5134 discloses ##STR12## 1a X=Et 1b X=i-Pr
for use in the synthesis of vinyl phosphonates via a Horner-Emmons reaction.
Callahan, L.; Ng, K.; Geller, D. H.; Agarwal, K.; Schwartz, N. B., Analytical Biochemistry 1989, 177, 67-71 discloses an analog of ADP (adenosine diphosphate) of the structure ##STR13##
U.S. application Ser. No. 109,762 filed Aug. 20, 1993, discloses squalene synthetase inhibitors having the structure ##STR14## wherein R.sup.2 is OR.sup.5 or R.sup.5a, R.sup.3 and R.sup.5 are independently H, alkyl, arylalkyl, aryl, cycloalkyl, metal ion or other pharmaceutically acceptable salt, or prodrug ester;
The R.sup.1 lipophilic group can be alkyl containing 7 to 25 carbons in the chain; alkenyl containing from 7 to 25 carbon atoms in the chain and from 1 to 6 double bonds; alkynyl containing 7 to 25 carbons in the chain and 1 to 6 triple bonds; mixed alkenyl-alkynyl containing 1 to 5 double bonds and 1 to 5 triple bonds; or aryl; and where in the above groups alkenyl, alkynyl and/or aryl may be substituted or unsubstituted; cycloheteroalkyl linked through a carbon on the ring or a heteroatom; cycloalkyl; heteroarylalkyl; cycloalkylalkyl; heteroaryl; cycloheteroalkylalkyl; or a group of the structure ##STR15## wherein Ar is aryl or heteroaryl, and Ar may include one to three additional rings fused to Ar, and wherein (CH.sub.2).sub.p contains from 1 to 15 carbons in the chain and may include 0, 1, 2 or 3 double bonds and/or 0, 1, 2 or 3 triple bonds in the normal chain, and may contain an ether or amino function in the chain, and/or may include 0, 1, 2 or 3 substituents as defined below for R.sup.6 ; and R.sup.6, R.sup.7, R.sup.8 and R.sup.8a are the same or different and are H, alkyl containing 1 to 40 carbons, alkoxy containing 1 to 40 carbons, alkenyl containing 2 to 40 carbons, alkenyloxy containing 2 to 40 carbons, alkynyl containing 2 to 40 carbons, alkynyloxy containing 2 to 40 carbons, hydroxy, halogen, nitro, amino, thiol, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, cycloalkyl, cycloatkylalkyl, Ar-alkyl, ArO, Ar-amino, Ar, Ar-thio, Ar-sulfinyl, Ar-sulfonyl, cyano, Ar-carbonyloxy, or Ar-carbonylamino.